Chemoselective isolation strategies to enable enrichment of subsets of molecules from complex mixtures including the hydroxyl moiety5 and the carboxylic acid group have been described previously6 (also PARTS A and B). Unlike traditional discovery methods that separate molecules by their physicochemical properties such as size or solubility, these methods facilitate separation of molecules based upon their functional group composition7 (also PARTS A and B). The devised reagents are polystyrene-based resin beads containing a chemoselective reactive group that captures only molecules that contain the targeted functionality, which remain affixed to the resin, while all others are washed away. The enriched subpool is subsequently released from resin yielding two distinct collections of molecules for biological testing.
In comparison to synthetic drugs, natural products contain a larger number of stereocenters, fewer nitrogen and sulfur atoms and more oxygen atoms, which are present in several functional groups including ethers, ketones, carboxylic acids and hydroxyls. While the carboxylic acid moiety is found in only ˜15% of natural products, providing a small group of compounds following enrichment, the hydroxyl is present in approximately 70% of all natural products.8 Accordingly, there is a need to develop an enrichment strategy capable of differentiating between aromatic and aliphatic alcohols, yielding two smaller subsets of molecules. Separation of phenols from the remaining hydroxyl pool would be advantageous because this functional group is prevalent in drugs9 and compounds containing these moieties possess antioxidant, antitumor, and antibacterial properties.10,11 Routine pH-mediated extraction techniques do not enable the separation of all phenols from aliphatic and carboxylic acid-containing compounds because the pKa values of these compounds span a wide range (Figure S1).12 In addition, use of anion exchange resin promotes simultaneous isolation of phenols and carboxylic acids.13 